I. What every physician needs to know.

Pulmonary alveolar proteinosis (PAP) is an exceedingly rare diffuse lung disease. It is characterized by abnormal accumulation of surfactant-related phopholipoprotein material within the alveoli.

Classification and pathogenesis

Significant advances in the understanding of the pathophysiology of PAP have occurred in the past decade, beginning with the observation that mice lacking granulocyte macrophage-colony stimulating factor (GM-CSF) exhibit a phenotype similar to human PAP.

Further studies exposed a crucial role for GM-CSF in the homeostatic clearance of alveolar surfactant; if not cleared, this presents as clinical manifestations of PAP. Importantly, a neutralizing GM-CSF antibody was identified in the serum of patients with acquired PAP, which now provides a new diagnostic tool for the disease.

PAP should be thought of as a clinicopathologic syndrome with heterogenous etiology. It is classified into three distinct types - primary (congenital), secondary and acquired.

A. Primary (congenital) pulmonary alveolar proteinosis

Congenital/hereditary PAP is extremely rare. Although histopathologically similar to the adult form of the disease, congenital PAP manifests in neonates and usually results in death within the first year of life. Numerous genetic mutations have been associated with congenital PAP, most transmitted in an autosomal recessive pattern.

B. Secondary pulmonary alveolar proteinosis

Secondary PAP describes the clinicopathologic syndrome when it is associated with another underlying disorder. A multitude of associations have been suggested, most falling under the broad categories of infection, systemic inflammation, malignancy or exogenous exposures. The nature of these associations with PAP and the underlying pathophysiology is poorly understood.

C. Acquired PAP

Acquired PAP is the most common and well-known form. The feature unique to acquired PAP is the presence of autoantibodies against GM-CSF in the serum and bronchoalveolar lavage (BAL) fluid of patients with the disease. Elegant studies have demonstrated that these antibodies inactivate GM-CSF in vitro as well as in vivo, impairing macrophage-dependent removal of surfactant-associated phospholipoproteins from the alveoli.

A diagnosis of PAP is established when a symptomatic patient is found to have characteristic findings on radiography, BAL and GM-CSF antibody testing.

A. History Part I: Pattern Recognition:

The clinical presentation of PAP is inconsistent and non-specific. Although most patients experience insidious onset of dyspnea, cough, exercise intolerance, or generalized malaise, some patients present with acute onset dyspnea or productive cough.

Interestingly, clinical symptoms are usually milder than the radiographic appearance would predict. Due to the vague and often indolent symptoms, the diagnosis is often delayed for months to years.

B. History Part 2: Prevalence:

PAP is a rare lung disease, with only about 500 cases reported in the literature. Median age of onset is 51 years, and male:female ratio is approximately 2:1. There is a strong association with tobacco use.

C. History Part 3: Competing diagnoses that can mimic pulmonary alveolar proteinosis.

The radiographic differential diagnosis for the "crazy-paving" pattern is broad, including infection (especially with Pneumocystis jirovecii), hemorrhage, neoplasm, and pulmonary edema.

D. Physical Examination Findings.

The physical exam is variable and unrevealing. A normal lung exam is the most common finding, although some patients may have crackles, clubbing or cyanosis.

E. What diagnostic tests should be performed?

There are no confirmatory diagnostic findings on physical exam.

F. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

GM-CSF autoantibodies

Serum levels of GM-CSF autoantibodies are elevated in patients with acquired PAP (but not congenital or secondary forms of the disease). Elevated levels of GM-CSF antibodies, in combination with compatible imaging and BAL findings can establish the diagnosis, eliminating the need for an open lung biopsy. It is important to note that low levels of GM-CSF antibodies are found in healthy patients.

G. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The classic HRCT finding is a "crazy-paving" pattern - patchy ground-glass opacities accompanied by smooth interlobular septal thickening (Figure 1). This finding however, is see in a variety of other conditions.

Figure 1.

H. What procedures should be performed?

Bronchoscopy with bronchoalveolar lavage is central to the diagnosis of PAP. BAL should be performed to exclude infection, hemorrhage or malignancy. BAL produces a characteristic dramatic milky fluid (Figure 2).

Figure 2.

Milky fluid from bronchoalveolar lavage

I. What is the gold standard for diagnosis?

Transbronchial, video-assisted thoracoscopic, or open-lung biopsy is the gold standard for diagnosing PAP. The characteristic histopathologic finding is alveolar filling with periodic acid-schiff-positive lipoproteinaceous material. The pulmonary architecture is generally well preserved without fibrosis.

III. Default Management.

Patients with congenital PAP usually die from hypoxic respiratory failure within the first year of life; treatment consists of supportive measures or double lung transplantation.

The mainstay of treatment in acquired PAP is the physical removal of lipoproteinaceous material via whole lung lavage (WLL) and GM-CSF supplementation. With current therapeutic strategies, survival in acquired PAP approximates that of an unaffected individual.

Whole lung lavage is the standard therapeutic procedure for PAP. Patients undergo general anesthesia, and a double-lumen endotracheal tube is placed, allowing simultaneous ventilation of one lung and "segmental flooding" of the other. Over several hours, up to 50 liters of saline are instilled in each lung to flush out the lipoproteinaceous debris. Clinical response has been reported to last a median of 15 months.

Granulocyte macrophage-colony stimulating factor augmentation

Discovery of the role of neutralizing GM-CSF antibodies in PAP has led to efforts to develop treatments that address the underlying pathophysiology. Exogenous GM-CSF, administered via inhaled or subcutaneous route, has resulted in a response rate of approximately 50% in published studies.

A. Immediate management.

Supportive care should be provided to maintain oxygenation.

B. Physical Examination Tips to Guide Management.

Pay special attention to breath sounds and oxygenation. Monitor closely for the development of signs and symptoms suggesting a superimposed infection.

C. Long-term management.

Double lung transplantation has been employed in rare cases of acquired PAP that fails to respond to WLL or progresses to pulmonary fibrosis. Of note, PAP has been reported to occur in the transplanted lungs, likely due to continued presence of GM-CSF autoantibodies.

A. Anticipated Length of Stay.

Length of stay depends on severity and disease and whether WLL will be performed during the hospitalization.

B. When is the Patient Ready for Discharge.

The patient can safely be discharged once oxygen requirements are stable, usually 24-48 hours after WLL.

C. Arranging for Clinic Follow-up

Patients should be followed closely by a pulmonologist within 2-4 weeks after discharge.

D. Prognosis and Patient Counseling.

With current therapeutic strategies, survival in acquired PAP approximates that of an unaffected individual. Tobacco cessation should be strongly encouraged and reinforced at every visit.

A. Core Indicator Standards and Documentation.

There are no specific quality indicators for managing PAP.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients hospitalized with PAP should be placed on chemical deep vein thrombosis (DVT) prophylaxis in the absence of contraindications. After discharge, consideration should be given to pulmonary rehabilitation, which may help improve functional status and reduce the risk of readmission.